tbuckley/cabot-search huggingface dataset:
Abstract LE03-01: Functional and computational approaches to uncover selection advantages of cancer aneuploidy
Authors: Alison Marie Taylor
Journal: Cancer Research (2022)

Abstract Aneuploidy, including the gain or loss of whole chromosomes or chromosome arms, is a near-universal feature of cancer. We previously applied methods that define chromosome arm aneuploidy to over 10,000 tumors in the Cancer Genome Atlas (TCGA). Cancer subtypes are often characterized by tumor specific patterns of chromosome arm copy number alterations and breakpoints; for example, squamous cell carcinomas (SCCs) from different tissues of origin are characterized by chromosome 3p (chr3p) loss and chromosome 3q (chr3q) gain. From the TCGA aneuploidy data, we developed an algorithm called BISCUT to distinguish peak regions of aneuploidy breakpoints on each chromosome arm. BISCUT identified loci affected by broad copy number alterations that provide fitness advantages or disadvantages both within individual cancer types and across cancers. Our analyses are consistent with selection being the primary driver of aneuploidy events in cancer. Recent advances in genome engineering allow generation of large chromosomal alterations and validation of findings from patient genomic data. We used the CRISPR-Cas9 system to delete one copy of chr3p in a human immortalized lung epithelial cell line similar to the putative cell-of-origin in lung SCC. Consistent with patient data, expression of chr3p genes was decreased upon deletion, as well as increased expression of interferon response genes. Cells with chr3p deletion initially proliferated more slowly than their siblings. Interestingly, after several passages in culture, this proliferation defect was rescued in chr3p deleted cells. Genome sequencing and karyotype analyses suggested that this was partially the result of chr3 duplication, with cells transitioning to a state of chr3q gain. Isolated cells with chr3q gain show deficiencies in squamous differentiation in organoid culture. Our genome engineering approach to model chromosome arm aneuploidies provides a robust model that will address a gap in our understanding of aneuploidy in cancer. Citation Format: Alison Marie Taylor. Functional and computational approaches to uncover selection advantages of cancer aneuploidy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LE03-01.
Abstract 6340: Deep, unbiased and peptide-centric plasma proteomics with differential analysis of proteoforms enabling proteogenomic studies of NSCLC at scale
Authors: Margaret Donovan, Henry Huang, John Blume, Marwin Ko, Ryan Benz, Theodore Platt, Juan Cuevas, Serafim Batzoglou, Asim Siddiqui, Omid Farokhzad
Journal: Cancer Research (2022)

Abstract Introduction: Comprehensive assessment of the proteome remains elusive because of proteoforms arising from alternative splicing, allelic variation, and protein modifications. Characterization of the variable protein forms, or proteoforms will expand our understanding of the molecular mechanisms underlying diseases, however requires unbiased protein coverage at sufficient scale. Scalable, deep and unbiased proteomics studies have been impractical due to cumbersome and lengthy workflows required for complex samples, like blood plasma. Here, we demonstrate the power of Proteograph in a proof-of-concept proteogenomic analysis of 80 healthy controls and 61 early-stage non-small-cell lung cancer (NSCLC) samples to dissect differences between protein isoforms arising from alternative gene splicing, as well as the identification of novel peptides arising from allelic variation. Materials, Methods and Results: Processing the 141 plasma samples with Proteograph yielded 21,959 peptides corresponding to 2,499 protein groups. Using peptides with significant abundance differences (p &amp;lt; 0.05; Benjamini-Hochberg corrected), we extracted proteins comprised of peptides where at least one peptide had significantly higher plasma abundance, and another significantly lower plasma abundance in controls vs. cancer, resulting in a set of putative proteoforms. For three of these proteins, the abundance variation is possibly explained by underlying protein isoforms. To identify protein variants, we performed exome sequencing on 29 individuals from the NSCLC study, created personalized mass spectrometry search libraries for each individual, and identified 464 protein variants. Conclusions: Proteograph can generate unbiased and deep plasma proteome profiles that enable identification of protein variants and peptides present in plasma, at a scale sufficient to enable population-scale proteomic studies. Citation Format: Margaret Donovan, Henry Huang, John Blume, Marwin Ko, Ryan Benz, Theodore Platt, Juan Cuevas, Serafim Batzoglou, Asim Siddiqui, Omid Farokhzad. Deep, unbiased and peptide-centric plasma proteomics with differential analysis of proteoforms enabling proteogenomic studies of NSCLC at scale [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6340.
Abstract 1352: <i>In vivo</i> CRISPR screening identifies mediators of immune evasion in KRAS-mutant lung cancer
Authors: Jesse Boumelha, Pablo Romero-Clavijo, Sophie de Carné, Miriam Molina-Arcas, Julian Downward
Journal: Cancer Research (2022)

Abstract Oncogenic KRAS mutations drive tumourigenesis in 30% of non-small cell lung cancer (NSCLC). Despite much effort, targeted therapies that aim to directly inhibit signalling pathways downstream of KRAS have limited clinical benefits for NSCLC patients, but the recent approval of PD-1/PD-L1 antibodies has led to striking durable responses. However, only a fraction of patients respond and therefore a deeper understanding of the mechanisms that drive immune evasion are required in order to broaden the clinical efficacy of immunotherapy. Increasing evidence suggests that oncogenic signalling pathways greatly influence the tumour immune landscape to impair anti-tumour immune responses. We therefore aim to understand the mechanisms by which KRAS signalling mediates immune evasion in lung cancer. Current mouse models of KRAS-mutant lung cancer are poorly immunogenic, limiting investigations into tumour-immune interactions. To overcome this, we generated a novel transplantable KRAS-mutant lung cancer model, KPAR1.3, which triggers spontaneous anti-tumour immune responses and is sensitive to immune checkpoint blockade. To identify mechanisms of immune evasion we carried out an in vivo pooled CRISPR-Cas9 screen targeting 240 KRAS-regulated genes using this novel immunogenic model. This identified the prostaglandin synthase COX-2 as a mediator of immune evasion and its expression was driven by KRAS in multiple models of mouse and human lung cancer. Loss of COX-2 promoted a pro-inflammatory tumour microenvironment and sensitised tumours to both innate and adaptive anti-tumour immune responses. Furthermore, therapeutic COX inhibition extended the survival of tumour-bearing mice and synergised with PD-1 blockade. Together these data suggest that targeting KRAS-driven mechanisms of immune evasion could broaden the clinical efficacy of immunotherapy in KRAS-mutant NSCLC. Since the approval of immunotherapy, a novel class of mutant-specific KRAS-G12C inhibitors have recently been approved for the treatment of KRAS-mutant NSCLC, however acquired drug resistance is common. We are therefore also currently investigating whether the inhibition of the COX-2/PGE2 axis enhances the therapeutic benefit of KRAS-G12C inhibitors. Citation Format: Jesse Boumelha, Pablo Romero-Clavijo, Sophie de Carné, Miriam Molina-Arcas, Julian Downward. In vivo CRISPR screening identifies mediators of immune evasion in KRAS-mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1352.
Abstract 358: Restoring necroptosis in colorectal cancer cells to overcome chemotherapeutic resistance
Authors: Kaylee Ermine, Dongshi Chen, Peng Wang, Jian Yu, Lin Zhang
Journal: Cancer Research (2022)

Abstract Colorectal cancer (CRC) is a leading cause of cancer related deaths in the United States. CRC patients are often treated with chemotherapeutic drugs, such as 5-fluorouracil (5-FU), and resistance to chemotherapy is a major clinical problem. It is well-established that 5-FU induces apoptosis in cancer cells, but apoptosis inhibition does not block the anticancer effect of 5-FU, suggesting a role of non-apoptotic cell death. Necroptosis is a regulated form of necrosis controlled by Receptor-Interacting Protein kinase 1 (RIP1), RIP3, and Mixed Lineage Kinase domain-Like (MLKL). TCGA RNA-Seq data reveal that RIP1 and RIP3 are frequently downregulated in CRC, with RIP3 downregulation correlating with worse clinical outcomes. We found that loss of RIP3 expression in CRC cells is associated with decreased 5-FU sensitivity. RIP3 silencing in CRC was shown to be caused by promoter hypermethylation. However, the exact functional role of RIP3 in response to anticancer therapies remains unclear. Our studies reveal that RIP3-expressing CRC cells were able to undergo both apoptosis and necroptosis in response to 5-FU treatment, which was abrogated upon knock-out or inhibition of RIP3. Restoration of RIP3 in RIP3-silenced CRC cells by transfection enhanced 5-FU sensitivity, along with restored necroptosis and enhanced apoptosis. Furthermore, we have shown that RIP3 expression can be restored in RIP3-silenced CRC cells by the DNA methyltransferase 1 inhibitor 5-aza-2’-deoxycytidine (5-aza-dC), which also enhances 5-FU sensitivity. This effect of 5-aza-dC is partially dependent on RIP3 and suppressed by a RIP3 inhibitor. Together, our results suggest RIP3 plays a critical role in response to 5-FU and other chemotherapeutic agents, and that restoring RIP3 expression can be used to potentiate chemotherapy. These results provide novel insight into the functional role of RIP3 in CRC chemotherapy, which could be explored for developing improved and personalized CRC treatments based on RIP3 status. Citation Format: Kaylee Ermine, Dongshi Chen, Peng Wang, Jian Yu, Lin Zhang. Restoring necroptosis in colorectal cancer cells to overcome chemotherapeutic resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 358.
Abstract 2819: Suppression of NKG2A mediated inhibition in <i>ex vivo</i> expanded natural killer cells increases their cytotoxicity
Authors: Tayler J. Croom-Perez, Liza D. Robles-Carrillo, Thomas A. Dieffenthaller, Alicja J. Copik
Journal: Cancer Research (2022)

Abstract In this study we propose to circumvent HLA-E/NKG2A mediated Natural Killer (NK) cell inhibition by suppression of NKG2A, to enhance cytotoxicity of ex vivo expanded NK cells. One mechanism employed by tumor cells to evade immunosurveillance is through induction of the surface expression of unconventional HLA ligands that agonize inhibitory receptors on immune cells. Specifically on some tumors, HLA-E is either expressed or its expression is known to be induced by IFNγ and is indicative of resistance to immunotherapy. HLA-E agonizes the CD94/NKG2A inhibitory complex on NK cells and some T cells to lessen their cytotoxicity, potentially decreasing the efficacy of cellular therapy with these immune cells. The CD94/NKG2A inhibitory complex is in balance with CD94/NKG2C stimulatory complex. HLA-E binds both of these complexes and the cytolytic activity of NK cells is influenced by the relative ratios of CD94 complexed to NKG2A or NKG2C. Thus, altering the ratio to increase NKG2C will increase NK cell cytotoxicity. In this study we show that NK cells ex vivo expanded with PM21-particle technology are highly cytotoxic and have elevated expression of NKG2A. These expanded NK cells also secrete high levels of IFNγ, inducing expression of HLA-E in tumor cells. To increase the cytotoxic potential of these ex vivo expanded NK cells, the potential to form CD94/NKG2A inhibitory complex was suppressed by either antibody blockade of NKG2A or deletion of the NKG2A gene by CRISPR/Cas9 editing. Cytotoxicity of NK cells against a lung cancer cell line stably expressing HLA-E were determined by kinetic live-cell imaging. Multiple NK cell:target (NK:T) ratios were used to show an increase in cytotoxicity over control NK cell conditions (alone or with isotype control) in the presence of NKG2A blocking antibodies with 39% increase observed at 1:10 NK:T ratio at 96h with anti-NKG2A and 56% increase with NKG2A knockout NK cells. These data suggest that blockade of CD94/NKG2A complex can improve cytotoxic activity of ex vivo expanded NK cells and could provide a promising effector population with the potential for enhanced therapeutic efficacy. Citation Format: Tayler J. Croom-Perez, Liza D. Robles-Carrillo, Thomas A. Dieffenthaller, Alicja J. Copik. Suppression of NKG2A mediated inhibition in ex vivo expanded natural killer cells increases their cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2819.
Abstract 5459: Synergistic effects of WX-0593 in combination with panitumumab on osimertinib-resistant <i>EGFR</i>-mutantnon-small cell lung cancer in vitro and in vivo
Authors: Shansong Zheng, Qingmei Zheng, Dongmei Chen, Xinmei Wang, Xin Dong, Xin Zhang, Cuicui Ma, Huicheng Duan, Chenwei Zhang
Journal: Cancer Research (2022)

Abstract Objective: To preliminarily demonstrate the synergistic effect of WX-0593 (anaplastic lymphoma kinase/ROS proto-oncogene 1 receptor tyrosine kinase [ALK/ROS1] tyrosine kinase inhibitor) in combination with panitumumab on osimertinib-resistant cis EGFR triple-mutant non-small cell lung cancer (NSCLC) both in vitro and in vivo. Methods: The tumor cell inhibition rates of WX-0593 and panitumumab alone or combined were assessed in osimertinib-resistant cis EGFR triple-mutant cell lines, including PC9 (EGFR Del19/T790M/C797S), NCI-H1975 (EGFR L858R/T790M/C797S), Ba/F3 (EGFR L858R/T790M/C797S and EGFR Del19/T790M/C797S). The in vivo tumor suppressive efficacy of single-agent WX-0593, panitumumab, and their combination was evaluated in H1975 (EGFR del19/T790M/C797S) and Ba/F3 (EGFR L858R/T790M/C797S) cell line-derived xenograft (CDX) models of BALB/c nude mice. The tolerability was also assessed. Results: In vitro studies showed that the combination of WX-0593 and panitumumab had a potent synergistic effect on proliferation inhibition in all the four cell lines with cis EGFR triple mutations resistant to osimertinib. WX-0593 in combination with panitumumab demonstrated a delaying effect on tumor growth without increasing drug toxicity in the H1975 CDX model. WX-0593 and panitumumab alone had tumor suppressive effects in the Ba/F3 CDX model. And WX-0593 plus panitumumab significantly enhanced the antitumor activity in the Ba/F3 model. Conclusion: The data from the study suggested that WX-0593 and panitumumab had a promising synergistic effect on osimertinib-resistant EGFR-mutant NSCLC both in vitro and in vivo. The combination regimen may have important clinical implications for the future treatment of patients with EGFR triple-mutant NSCLC resistant to osimertinib. Citation Format: Shansong Zheng, Qingmei Zheng, Dongmei Chen, Xinmei Wang, Xin Dong, Xin Zhang, Cuicui Ma, Huicheng Duan, Chenwei Zhang. Synergistic effects of WX-0593 in combination with panitumumab on osimertinib-resistant EGFR-mutantnon-small cell lung cancer in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5459.
Abstract LB159: Neighborhood obesogenic environment and risk of prostate cancer: The Multiethnic Cohort
Authors: Mindy C. Hebert-DeRouen, Li Tao, Salma Shariff-Marco, Juan Yan, Yurii B. Shvetsov, Song-Yi Park, Cheryl L. Albright, Kristine Monroe, Loic Le Marchand, Lynne Wilkens, Scarlett L. Gomez, Iona Cheng
Journal: Cancer Research (2022)

Abstract Background: Obesity is associated with risk of aggressive prostate cancer. It is not known whether neighborhood obesogenic factors are associated with prostate cancer risk. Methods: Neighborhood socioeconomic status (nSES) and four neighborhood obesogenic environment factors (urbanicity, mixed-land development, unhealthy food environment, and parks) were assessed for associations with prostate cancer risk among 41,563 African American, European American, Japanese American, and Latino males in the Multiethnic Cohort Study (MEC), California site. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for non-aggressive and aggressive prostate cancer, adjusting for individual-level sociodemographic, behavioral, and prostate cancer risk factors. Analyses were stratified by race, ethnicity, and, among Latino males, nativity. Results: Males residing in low SES, compared to high SES, neighborhoods had lower risk of non-aggressive prostate cancer (lowest vs. highest quintile HR=0.81; 95% CI=0.68, 0.95, p-trend 0.024); driven by a similar trend among U.S.-born and foreign-born Latino males. Foreign-born Latino males in neighborhoods with low mixed-land development had increased risk (lowest vs. highest quintile HR=1.52; 95% CI=1.09, 2.12). African American males in neighborhoods with more unhealthy food environments had increased risk of aggressive disease (more vs. none, HR=1.35; 95% CI=1.02, 1.77). Conclusions: Neighborhood SES and obesogenic factors were independently associated with prostate cancer risk; associations varied by race, ethnicity, nativity, and disease aggressiveness. Impact: Upstream structural and social determinants of health that contribute to neighborhood obesogenic characteristics likely impact prostate cancer risk differently across groups defined by race, ethnicity, and nativity and by disease aggressiveness. Citation Format: Mindy C. Hebert-DeRouen, Li Tao, Salma Shariff-Marco, Juan Yan, Yurii B. Shvetsov, Song-Yi Park, Cheryl L. Albright, Kristine Monroe, Loic Le Marchand, Lynne Wilkens, Scarlett L. Gomez, Iona Cheng. Neighborhood obesogenic environment and risk of prostate cancer: The Multiethnic Cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB159.
Abstract 774: Microdissected gene expression profiling of recurrent nasopharyngeal carcinoma
Authors: Joshua Tay, Wei Keat Teo, Chuan Keng Goh, Bing Cheng Wu, Kwok Seng Loh
Journal: Cancer Research (2022)

Abstract Nasopharyngeal cancer (NPC) is an EBV-driven epithelial carcinoma with a recurrence rate of 30%. Biological pathways and predictive markers for recurrence remain understudied. Further, NPC tumors are associated with an intense inflammatory infiltrate, masking gene expression signals from the tumor epithelial compartment. We perform laser-capture microdissection on a preliminary cohort of 12 tumors, including primary tumors from recurrent and non-recurrent cases matched for stage of disease. Smart-3SEQ, a novel 3’ end RNA-Seq technique which allows for the accurate quantification of transcript abundance in FFPE samples, was performed to obtain gene expression libraries. Tumor epithelial and microenvironment regions from were separately microdissected, giving a total of 42 histologically-pure gene expression libraries. Raw reads were mapped to the human hg19 and EBV genomes and gene expression counts were obtained with Subread. Differential gene expression and gene set enrichment was performed in R with DESeq2 and fgsea respectively. We observed that primary NPC tumors that did not recur were significantly enriched for immune processes, including leukocyte mediated immunity, innate immune response and lymphocyte activation (padj &amp;lt; 1E-9 for all). The top differentially expressed genes in this group included mediators of inflammation such as STAT1 (padj = 0.0204). Critically, these gene expression changes were observed within the tumor epithelial compartment. In contrast, primary NPC tumors that eventually recurred were enriched for known oncogenes including BCL2 (padj = 0.000420). These findings suggest that heterogeneity in gene expression between NPC tumors play an important role in treatment response. Further work to define gene expression subtypes of NPC tumors will be helpful for patient stratification and personalized care. Citation Format: Joshua Tay, Wei Keat Teo, Chuan Keng Goh, Bing Cheng Wu, Kwok Seng Loh. Microdissected gene expression profiling of recurrent nasopharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 774.
Abstract 5599: A novel orally available anti-cancer drug candidate, SB17170, represses myeloid-derived suppressor cells by targeting HMGB1
Authors: Young Il Choi, Sungoh Ahn, Hyo Young Kim, Na Jin Jung, Jae Jin Lee, Seung Bum Park
Journal: Cancer Research (2022)

Abstract Introduction: High Mobility Group Box1 (HMGB1) is a kind of DAMP to modulate immune responses in various conditions, including the tumor microenvironment. In various cancers, it has been reported that cytoplasmic localization of HMGB1 is correlated with poor prognosis. Here, we present a novel small-molecule drug candidate, SB17170, which inhibits immune-suppressive cells in tumor microenvironments by specific binding to HMGB1. Methods: SB17170 is a pro-drug of active metabolite SB1703 which was identified in cell-based phenotypic screening. SB1703 modulates immune responses by inhibiting the secretion of various cytokines from activated macrophages. HMGB1 was revealed as the target protein of SB1703 using Fluorescence difference In Two-dimensional Gel-Electrophoresis (FITGE). The antitumor activity of SB1703 was analyzed in B16F10 murine syngeneic model. Results: SB17170 is orally available drug candidate at the clinical development stage for solid tumors. The active metabolite SB1703, bound to HMGB1, was observed in activated MDSC, but not in immature MDSC, and inhibited the activity and cytokine release of MDSC at the submicromolar range. The antitumor activity of SB17170 was observed in B16F10 murine syngeneic model, but not in immunodeficient NOG model, suggesting that SB17170 requires the adaptive immune system for its antitumor activity. The oral treatment of SB17170 in tumor-bearing mice induced intratumor T cell infiltration, but reduced the number of MDSC from day 3. SB17170 also repressed HMGB1 levels as well as MDSC in the blood. In combination with immune checkpoint inhibitors against PD1, PD-L1, and CTLA4, SB17170 enhanced the antitumor responses. Conclusions: We presented here orally available small-molecule drug candidate, SB17170, which selectively binds to HMGB1 and represses MDSC in tumor microenvironment. SB17170 showed the antitumor activity in B16F10 murine syngeneic models, but not in immunodeficient background, suggesting that its mechanism of action is based on antitumor immune responses. Citation Format: Young Il Choi, Sungoh Ahn, Hyo Young Kim, Na Jin Jung, Jae Jin Lee, Seung Bum Park. A novel orally available anti-cancer drug candidate, SB17170, represses myeloid-derived suppressor cells by targeting HMGB1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5599.